Citations

Objective: In this study, we evaluate the utility of ctDNA analysis in a large cohort of patients for whom ctDNA testing was ordered commercially with real-world application. Summary Background Data: Circulating tumor DNA (ctDNA) has emerged as a prognostic and predictive biomarker for assessing post-surgical molecular residual disease (MRD) and response to treatment. Methods: A real-world data analysis was performed using commercial ctDNA testing (SignateraTM) from patients (N=795, n=5,971 plasma samples) with stage I-III colon cancer treated at multiple US institutions. The association of ctDNA detection within the MRD window, during surveillance, and the impact of ACT was correlated with patient outcomes. Results: ctDNA-positive patients during the MRD window and surveillance showed significantly shorter DFS compared to ctDNA-negative patients (hazard ratio (HR): 9.85, P<0.0001; HR: 26.91, P<0.0001). Multivariate analysis of the MRD window revealed ctDNA-positivity as the most significant factor associated with inferior DFS (adjHR: 7.7, P<0.001). MRD-positive patients who received ACT showed improved DFS compared to patients observed post-surgery (adjHR: 6.1, FDR adj P=0.0007). No ACT benefit was observed in MRD-negative patients (adj HR: 1.20, FDR adj P=0.768). On evaluating ctDNA dynamics from MRD to surveillance, patients who remained ctDNA-positive or converted from negative to positive showed a significantly inferior DFS (HR: 34.40, P<0.0001; HR: 13.65, P<0.0001) compared to persistently ctDNA-negative patients. Conclusions: Postsurgical ctDNA detection is prognostic of relapse and potentially predictive of ACT benefit in patients with resectable colon cancer, which may enable personalized surveillance, intervention, and/or trial options, ultimately improving patient outcomes.

This study aimed to determine if extended infusion (EI; over > 3 hr) beta-lactam therapy increased IV access requirements compared with traditional dosing (TD; over 30 min). Eighty-six adult ICU patients treated with TD anti-pseudomonal beta-lactams who underwent therapeutic drug monitoring (TDM) were included. Patients who transitioned from TD to EI after TDM (EI group) were matched 1:1 to patients who remained on TD. In the primary analysis, the median (interquartile range) total number of lumens in the 24 hours before TDM compared with the 48 hours after TDM were similar between groups (pre: TD 3 [2–5] vs. EI 4 [3–5]; p = 0.22 and post: TD 3 [2–4] vs. EI 4 [3–5]; p = 0.05). Delivery of beta-lactams via EI was not associated with a need for more IV access. Practical challenges such as access should not limit use of EI beta-lactams when indicated.

Background: Thrombotic thrombocytopenic purpura (TTP) is a life-threatening hematologic emergency caused by ADAMTS13 deficiency, leading to microvascular thrombosis, haemolytic anaemia, thrombocytopenia, and end-organ damage. Neurological symptoms occur in up to 90% of cases and are frequently misdiagnosed as stroke. Prompt recognition and treatment reduce the mortality rate from over 90% to 10–20%. Case presentation: A 70-year-old woman with no significant medical history presented with acute aphasia and right-sided facial and upper extremity numbness. Five days prior, she had experienced fatigue, headache, and bruising. On admission, she had stable vitals with mild aphasia and purpuric ecchymoses noted on examination. Laboratory findings revealed haemolytic anaemia (haemoglobin 7.8 g/dl, lactate dehydrogenase 875 U/l, total bilirubin 2.4 mg/dl), thrombocytopenia (35 ×109/l), and unremarkable coagulation studies (partial thromboplastin time 30 sec, prothrombin time-international normalized ratio 1, fibrinogen 370 mg/dl, D-dimer 2.15 ng/ml). Peripheral smear showed no schistocytes but noted 2+spherocytes. Stroke was ruled out with brain magnetic resonance imaging/magnetic resonance angiography. Given the bicytopenia with possible haemolysis along with new neurological symptoms, TTP was considered in the differential diagnosis. A PLASMIC score of 5 suggested a high probability of TTP. Plasma exchange and corticosteroids were initiated within 5 hours of presentation. ADAMTS13 activity <1% confirmed the diagnosis 4 days after presentation. After five plasma exchange sessions, the patient’s platelet count normalized and neurologic deficits resolved by discharge. Conclusion: This case underscores the importance of considering TTP in stroke mimics, even in the absence of schistocytes, if clinical suspicion is high. Early recognition and initiation of treatment significantly improve patient outcomes.

BACKGROUND/OBJECTIVE Patient- and family-centered rounds (PFCR) have become a pediatric standard of care. However, rounds experiences of families using languages other than English (LOE)—particularly languages other than English or Spanish (LOES; eg, Arabic)—receive less focus. We aimed to identify differences in PFCR communication and engagement by language. METHODS We analyzed postintervention data from a 21-center structured PFCR study, assessing communication practices, quality, and family and nurse engagement during PFCR. Logistic regression adjusted by site compared PFCR between families using (1) LOE vs English, (2) Spanish vs English, and (3) LOES vs English. RESULTS Among 3051 PFCR encounters, 348 (11.4%) involved LOE (Spanish = 260; LOES = 85). Interpretation was not used in 7.2%, 5.8%, and 9.4% of encounters using LOE, Spanish, and LOES, respectively. PFCR in the following groups had lower adjusted odds (adjusted odds ratio [95% CI]) for the following domains: (1) LOE vs English: including providing verbal patient summaries (0.66 [0.46–0.95]), explaining diagnoses and differentials (0.62 [0.44–0.88]), family engagement (0.34 [0.20–0.57]), nursing inclusion (0.75 [0.60–0.93]), and nursing engagement (0.69 [0.52–0.90]). (2) Spanish vs English: diagnoses/differentials being explained (0.56 [0.37–0.85]), family engagement (0.35 [0.18–0.67]), nursing inclusion (0.77 [0.59–1.00]), and nursing engagement (0.68 [0.52–0.89]). (3) LOES vs English: families sharing concerns (0.66 [0.47–0.93]), family engagement (0.30 [0.16–0.54]), and nursing inclusion (0.74 [0.55–0.99]). CONCLUSION Even after implementing a PFCR intervention, families using LOE—especially LOES—experienced significant disparities in communication and engagement. Future approaches to improving PFCR should emphasize language access and promote nurse and family engagement for families using LOE, particularly LOES.

Abstract Background Methylation class pleomorphic xanthoastrocytoma (mcPXA) comprises tumors with the DNA methylation signature of classical PXA but with a wider histologic spectrum, including overlap with glioblastoma (GBM). Methods To clarify the histologic and molecular scope of mcPXA and characterize its clinical behavior, a cohort of 469 tumor samples from 458 patients matching to mcPXA by the DKFZ classifier (v12.6 score ≥0.85) was interrogated. Results Patient median age was 23 years (range 1-73 years) with a female predominance (259 female/199 male). CDKN2A/B homozygous deletion was observed in 406 of 469 (87%) samples. In samples tested for BRAF p.V600E mutations (n = 279), 240 (86%) harbored the mutation. A chr7+/chr10− pattern was observed in 103 of 469 (22%) samples. Among samples tested for TERT promoter mutations (n = 143), 32 (22%) harbored the mutation. Progression-free and overall survival of patients with mcPXA were comparable to patients with methylation class IDH-mutant astrocytoma, low grade, but a GBM-like subset (ie, cases with a pre-methylation working diagnosis of GBM) showed shorter survival. Histologic features of high grade, including palisading necrosis and microvascular proliferation, were prognostic in mcPXA. Compared to patients with BRAF p.V600E-altered GBM, patients with mcPXA were younger and had a lower frequency of TERT promoter mutations. Conclusion Tumors in mcPXA share molecular characteristics with histologically defined PXA, and high-grade histologic features can help predict their clinical behavior. The use of an epigenetic classification of PXA reveals that this group of tumors is more common than previously appreciated and warrants in-depth study to identify efficacious therapeutic options.

ABSTRACT Periprosthetic joint infection (PJI) is a serious complication of total joint arthroplasty (TJA), with Staphylococcus aureus being one of the most common causative organisms. Irrigation and debridement with component retention (IDCR) is often performed to manage PJI. Antimicrobial treatment that targets S. aureus biofilms on prosthesis surfaces and within bone may be especially helpful when retaining a prosthesis. Phages, viruses that specifically infect bacteria, are a potential therapeutic consideration. Using a biofilm time kill assay in bovine synovial fluid, bactericidal activity of vancomycin or phage K (32 µg/mL and 10 11 pfu/mL, respectively) as well as the combination of phage K (10 10 pfu/mL) and vancomycin (32 µg/mL) was observed against a methicillin‐resistant S. aureus (MRSA) strain. Using a murine PJI model, mice infected with MRSA underwent IDCR followed by phage administration into the joint space with or without systemically administered vancomycin. Mice receiving both phage and vancomycin had significant reductions in MRSA on the prosthesis surface compared to untreated or vancomycin‐treated mice. Phage K showed bactericidal activity in vitro and was active when locally delivered in combination with systemically administered vancomycin in a murine PJI model managed with IDCR.

Mechanical stretch associated with respiratory support can impair airway development and function in neonates, but the mechanisms are not fully understood. Using developing human airway smooth muscle cells exposed to cyclic forces with static stretch to mimic continuous positive airway pressure, we found that stretch dysregulates long-term cell proliferation and inflammatory cytokine production, and mechanosensitive Piezo ion channels may play a role in the proliferation response.

ABSTRACTPortopulmonary hypertension (PoPH), a type of pulmonary arterial hypertension (PAH) in patients with liver disease, is associated with high morbidity and mortality. The relationship between cardiopulmonary hemodynamics, PAH therapy, and survival in PoPH remains unclear. We performed a retrospective cohort study of PoPH patients from the international pulmonary hypertension (PH) meta‐registry, PVRI GoDeep. PAH was defined by a mean pulmonary arterial pressure > 20 mmHg, pulmonary arterial wedge pressure ≤ 15 mmHg, and a pulmonary vascular resistance (PVR) > 2 Wood Units. PoPH diagnoses were assigned by each center's PH specialist based on international guidelines at the time of enrollment. 246 incident PoPH patients met eligibility criteria and were included in the analysis, equally split between males (51%) and females (49%), with a median age of 54 years. When compared to both patients with IPAH and those with other subtypes of PAH (not classified as PoPH or IPAH), those with PoPH had significantly lower 5‐year survival rates (46% vs. 68% vs. 65%, log‐rank p < 0.001). Amongst the PoPH patients, however, there was no significant difference in 5‐year survival when dichotomized by disease severity, either by a PVR of 5 Wood Units or a CI of 2.5 L/min/m2. Treatment of the PoPH patients with PAH‐targeted therapies was associated with significantly higher 5‐year survival rates compared to those not receiving such treatments, as shown by Kaplan–Meier analysis. This survival benefit was observed for PDE5i (50% vs. 34%, log‐rank p = 0.029), ERA (58% vs. 34%, log‐rank p < 0.001), and the combination of PDE5i and/or ERA (51% vs. 22%, log‐rank p < 0.001), as well as any PAH‐targeting treatment (50% vs. 26%, log‐rank p = 0.007). Corresponding survival advantage was noted when including only PoPH patients with MELD Score ≥ 13. PoPH is a disease with significantly worse long‐term survival than other PAH subtypes, but targeted PAH therapy is associated with a robust survival benefit. Survival did not differ across high‐risk PVR and cardiac index thresholds, suggesting the factors that influence prognosis and survival in PoPH may be unique as compared to other PAH subtypes, and warrant further investigation.

BACKGROUND AND OBJECTIVES: Gynecological cancers represent 10% to 15% of cancers in women, but brain metastases (BM) are uncommon, with limited evidence regarding their management. This study investigates the role of stereotactic radiosurgery (SRS) for BM from primary gynecological cancers. METHODS: Institutions of the International Radiosurgery Research Foundation participated in this study. Inclusion criteria required histological diagnosis of epithelial ovarian, cervical, or endometrial cancer, SRS between 2000 and 2020, and at least 1 imaging or clinical follow-up. RESULTS: A total of 276 patients having SRS for 977 BM were included. Median age at SRS was 62 years (IQR, 55-70). Primary cancer origin was ovarian in 128 (46%), cervical in 43 (16%), and endometrial in 105 patients (38%). Median Karnofsky Performance Scale was 80%, and systemic disease was active in 124 (45%) of patients. A median of 1 metastasis was treated (IQR, 1-3) per patient. Median individual metastasis volume was 0.27 cc (IQR, 0.05-1.59 cc). The majority (91%) received single-fraction SRS, using a median margin dose of 18 Gy (IQR, 16-20 Gy). Actuarial overall survival was 77%, 65%, and 44% at 6, 12, and 24 months, respectively. Predictors of worsened survival included older age, cervical and endometrial primary, previous whole-brain radiation therapy (WBRT), active systemic disease, worsened Karnofsky Performance Scale, absence of subsequent surgery, and increasing number of BM. Actuarial local control was 94% at 6 months, 89% at 12 months, and 78% at 24 months. Previous SRS or WBRT, tumor bed treatment, and cervical histology increased the risk of local failure. New remote BM and leptomeningeal dissemination occurred in 44% and 11% of patients, respectively. Adverse radiation effects (ARE) occurred in 13% of cases but were symptomatic in only 3%. Previous WBRT or SRS and increased tumor diameter increased the risk of ARE. CONCLUSION: SRS is an effective management for BM from gynecological cancers with low risks of symptomatic ARE.